MXPA99010450A - N-triazolyl-2-indolecarboxamides and their use as cck-a agonists - Google Patents

Abstract

The invention concerns compounds of formula (I) in which R1, R4, X1, X2, X3, X4, Y1, Y2 and Y3 are as defined in claim 1. These compounds have partial or total agonist activity of CCK-A receptors and are useful for treating eating problems, obesity, tardive dyskinesia and disorders of the gastrointestinal sphere.

Description

N-TRIAZOLIL-2-INDOLCABOXAMIDAS AND ITS USE AS AGONISTS OF CCK-A DESCRIPTION OF THE INVENTION The present invention relates to new triazole derivatives, to a process for their preparation and to the medicaments containing them. More particularly, the subject of the present invention is new non-peptide compounds that have affinity to cholecystokinin (CCK) receptors. CCK is a peptide that, in response to a food intake, is secreted at the peripheral level and participates in the regulation of numerous digestive processes (Crawley J. N. et al., Peptides, 1994, 15 (4), 731-735). Subsequently, CCK has been identified in the brain, and could be the most abundant neuropeptide that acts as a neuromodulator of brain functions by stimulation of CCK-B type receptors (Crawley JN et al., Peptides, 1994, 15 (4). ), 731-735). In the central nervous system, CCK interacts with neuronal transmission mediated by dopamine (Crawley J. N. al., ISIS Atlas of Sci., Pharmac, 1988, 84-90). It also participates in mechanisms involving acetylcholine, gaba (4-aminobutyric acid), serotonin, opioids, somatostatin, substance P and also in ion channels.

Its administration causes physiological changes: palpebral ptosis, hypothermia, hyperglycemia, catalepsy; and behavioral modifications: hipolocomotricity, decreased exploration, analgesia, modification of the learning ability, sexual behavior modification and satiety. CCK exerts its biological activity through, at least, two types of receptors: the CCK-A receptors located mainly in the periphery, and the CCK-B receptors present essentially in the cerebral cortex. Peripheral-type CCK-A receptors are also present in certain areas of the central nervous system that include the postrema area, the solitary tract nucleus, and the interpeduncular nucleus (Moran TH et al., Brain Research, 1986, 362, 175- 179; Hill DR et al., J. Neurosci, 1990, 10, 1070-1081), however with species differences (Hill DR et al., J. Neurosci, 1990, 10, 1070-1081); Mailleux P. er al., Neurosci Lett., I99O, 117, 243-247; Barrett R. W. et al., Mol. Pharmacol., 1989, 36, 285-290; Mercer J. G. et al., Neurosci Lett., 1992, 137, 229-231, Moran T. H. et al., Trends in Pharmacol. Sci., 1991, 12, 232-236). In the periphery, through the CCK-A receivers (Moran TH et al., Brain Research, 1986, 362, 175-179), CCK delays gastric emptying, modulates intestinal motility, stimulates vesicular contraction, increases biliary secretion, controls pancreatic secretion (McHugh PR et al. ., Fed. Proc., 1986, 45, 1384-1390; Pendleton RG et al., J. Pharmacol. Exp. Ther., 1987, 241, 110-116). The CCK could act in certain cases on blood pressure and influence the immune systems. The role of CCK in the satiety signal is based on the fact that the plasma concentrations of CCK, which are dependent on the composition of the meals (high concentrations of proteins or lipids), are higher than those observed before meals after meals. (Izzo RS et al., Regul. Pept., 1984, 9, 21-34; Pfeiffer A. et al., Eur. J. Clin. Invest., 1993, 23, 57-62; Lieverse RJ Gut. 1994, 35, 501).

In bulimics, there is a decrease in the secretion of CCK induced by a meal, (Geraciotti TD Jr. et al., N. Engl. J. Med., 1988, 319, 683-688; Devlin MJ et al., Am. J. Clin. Nutr., 1997, 65, 114-120) and a decrease in CCK concentrations in the cerebrospinal fluid (Lydiard RB et al., Am. J. Psychiatry, 1993, 150, 1099-1101). In T lymphocytes, a cellular compartment where central neuronal secretions can be reflected, baseline CCK concentrations are significantly lower in patients affected by Bulimia nervosa (Brambilla F. et al., Psychiatry Research, 1995, 37, 51-56). . Treatments (for example by L-henilalanine, or trypsin inhibitors) that increase the secretion of endogenous CCK, cause a reduction in dietary intake in several species, including man (Hill AJ et al., Physiol. Behav 1990, 48, 241-246, Ballinger AB et al., Metabolism 1994, 43, 735-738). Also, the administration of exogenous CCK reduces food intake in numerous species including man (Crawley J. N. et al., Peptides 1994, 15, 731-755). Inhibition of food intake by CCK is due to mediation of the CCK-A receptor. Indeed, devazepide, a selective antagonist of CCK-A receptors, inhibits the anorectic effect of CCK while selective agonists of those receptors inhibit food intake (Asin KE et al., Pharmacol. Biochem. Behav., 1992, 42, 699-704; Elliott RL et al., J. Med. Chem. 1994, 37, 309-313; Elliott RL et al., J.

Med. Chem. 1994, 37, 1562-1568). In addition, OLEFT rats, which do not express the CCK-A receptor, are insensitive to the anorectic effect of CCK (Miyasaka K. et al., 1994, 180, 143-146). Based on these evidences about the key role of CCK in the signal of peripheral satiety, the usefulness of agonists and antagonists of CCK as a drug in the treatment of some disorders of eating behavior, obesity and diabetes is indisputable. An agonist of CCK receptors can also be used in therapy in the treatment of emotional, sexual and amnestic behavior disorders (Itoh S. et al., Drug, Develop, Res., 1990, 21, 257-276), of schizophrenia, of psychoses (Crawley JN et al., Isis Atlas of Sci., Pharmac, 1988, 8490 and Crawley JN, Trends in Pharmacol. Sci., 1991, 12, 232-265), of Parkinson's disease (Bednar I. et al., Biogenic amine, 1996, 12 (4), 275-284), of dyskinesis late (Nishikawa T. et al., Prog. Neuropsychopharmacol. Biol. Psych., 1988, 12, 803-812; Kampen JV et al., Eur. J. Pharmacoi., 1996, 298, 7-15) and various disorders of the gastrointestinal sphere (Drugs of the Future, 1992, 17 (3), 197-206). The CCK receptor agonists CCK-A are described in the literature. For example, certain products having such properties are described in EP383690 and WO90 / 06937, W095 / 28419, WO96 / 11701 or also W096 / 11940. Most of the CCK-A agonists described to date are peptidic in nature. In this way, FPL 14294 derived from CCK-7 is a potent non-selective CCK-A agonist against CCK-B receptors. It possesses a potent inhibitory activity of food intake in the rat and in the dog after its intranasal administration (Simmons RD et al., Pharmacol., Biochem. Behav., 1994, 47 (3), 701-708; Kaiser EF et al. al., Faseb, 1991, 5, A864). Likewise, it has been shown that A-71623, a selective tetrapeptide agonist of CCK-A receptors, is effective in anorexia models over a period of 11 days and leads to a significant reduction in weight gain with respect to control in rodents and cinomologos monkeys (Asín KE et al., Pharmacol.

Biochem. Behav., 1992, 42, 699-704). Similarly, structural analogs of A 71623, which possess good efficacy and selectivity for CCK-A receptors, are endowed with potent anorectic activity in the rat (Elliott RL et al., J. Med. Chem., 1994, 37, 1562-1568). GW 7854 (Hirst G. C. et al., J.

Med. Chem., 1996, 39, 5236-5245), a benzodiazepine-1, 5, is an agonist of the CCK-A receptors in vitro. This molecule is also active orally, in the contraction of the gallbladder in the mouse and in the food intake in the rat. It has now surprisingly been discovered that a series of triazole derivatives possess partial or total agonist activity of the CCK-A receptors. The compounds according to the invention have been subjected to systematic studies to characterize: - their potential to displace [1251] -CCK from the binding sites present in rat pancreatic membranes (CCK-A receptor) or from 3T3 cells expressing the recombinant human CCK-A receptor; - its affinity for the CCK-B receptor, present in guinea pig cortex membranes, with some of the compounds, selective or non-selective ligands, of the CCK-A receptors; - its agonist property of CCK-A receptors due to its ability to induce in vitro, intracellular calcium mobilization in 3T3 cells that express the human CCK-A receptor. The triazole derivatives, according to the invention, are CCK-A agonists, since they are able to partially or totally stimulate, such as CCK, the mobilization of intracellular calcium in a cell line expressing the recombinant human CCK-A receptor. . They are, surprisingly, much more powerful than derivatives: thiazole described in patent applications EP518731, EP611766; of thiadiazole, described in patent application EP620221; of the benzodiazepines described in EP667344. Indeed, these thiazole, thiazole and benzodiazepine derivatives are unable to induce this mobilization of intracellular calcium mediated by the CCK-A receptor. The triazole derivatives according to the invention are also much more potent than those thiazole, thiadiazole or benzodiazepine derivatives for their ability to block in vivo, intraperitoneally, the gastric emptying in the mouse. In this way, the CCK-A agonist properties have been studied in vivo, evaluating their ability to block gastric emptying in the mouse or to provoke, always in vivo, the emptying of the gallbladder in the mouse. Some derivatives also have an antagonistic activity of the CCK-B receptors. Therefore, the present invention relates to compounds of formula: wherein: - R. represents a (C2-C6) alkyl; a group - (CH2) n-G where n ranges from 0 to 5 and G represents a non-aromatic mono- or polycyclic hydrocarbon group at C3-C13 optionally substituted by one or more (C1-C3) alkyi; a phenyl (C1-C3) alkyl in which the phenyl group is optionally substituted once or several times by a halogen, by a (C1-C3) alkyl or by a (0, -03) 8100x1; a group - (CH2) nNR2R3 in which n represents an integer from 1 to 6 and R2 and R3 identical or different represent a (C1-C3) alkyl or constitute with the nitrogen atom to which a morpholino, piperidino group is attached , pyrrolidinyl or piperazinyl; X. ,, X2, X3 or X4 each independently represents a hydrogen atom, a halogen atom, a (C, -C6) alkyl, a (C, -C3) alkoxy or a trifluoromethyl; it is understood that a single one between X1t X2, X3 or X4 represents possibly a hydrogen atom; - R4 represents hydrogen, a group - (CH2) nCOOR5 in which n is as defined above and R5 represents a hydrogen atom, a - (C1-C6) alkyl or an - (C6-C10) aryl- ( C1-C6) alkyl; a (C, -C6) alkyl; a group - (CH2) nOR5 or a group - (CH2) nNR2R3 in which n, R2, R3 and R5 are as defined above; a - (CH2) n-tetrazolyl group in which n is as defined above, or R4 represents one of those groups in the form of an alkali metal or alkaline earth metal salt; Y ,, Y2 and Y3 independently represent a hydrogen, a halogen, a (C1-C3) alkyl; a (C, -C3) alkoxy, a nitro, a cyano, (C ^ CeJacylamino, carbamoyl, trifluoromethyl, a group COOR6 in which R6 represents hydrogen, 0 (C1-C3) alkyl, or one of its salts or solvates According to the present invention, "(C1-C6) alkyl" or "(C2-C6) alkyl" means a linear or branched alkyl having 1 to 6 carbon atoms or 2 to 6 carbon atoms respectively The alkoxy radical designates an alkyloxy radical in which alkyl is as defined above The acyl radical designates an alkylcarbonyl radical in which alkyl is as defined above (CT-CeJacylamino is an alkylcarbonylamino radical in The non-aromatic C3-C13 hydrocarbon groups comprise mono- or polycyclic, condensed or bridged, saturated or unsaturated, optionally terpene radicals, which radicals are optionally mono- or poly-substituted by a (C., - C3) alkyl The monocyclic radicals include cycloalkyls, for example eg: cicloproilos, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclododecyl. Polycyclic radicals include, for example: norbornane, adamantane, hexahydroindane, norbornene, dihydrophenalene, bicyclo [2.2.1 jheptane, bicyclo [3.3.1 jonane; tricycle [5.2.1.02'6] dean. According to the present invention, halogen is means an atom chosen from fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine. Examples of aryl groups are phenyl and naphthyl. The alkali metal or alkaline earth metal cations are preferably chosen from sodium, potassium or calcium. When a compound according to the invention has one or two asymmetric carbons, the optical isomers of that compound form an integral part of the invention. When a compound according to the invention exhibits stereoisometry, for example of the axial-equatorial type, the invention comprises all the stereoisomers of that compound. The salts of the compounds of formula (I) according to the present invention comprise those with mineral or organic acids which allow a convenient separation or crystallization of the compounds of formula (I), such as picric acid, oxalic acid or an optically active acid, for example a tartaric acid, a dibenzoyltartric acid, a mandelic acid or a camphorsulfonic acid, and those which form physiologically acceptable salts, such as the hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogen phosphate, maleate, fumarate, 2- naphthalene sulfonate, paratoluenesulfonate. The salts of the compounds of formula (I) also include salts with organic or mineral bases, for example alkali metal or alkaline earth metal salts, such as sodium, potassium or calcium salts, the sodium salts and sodium salts being preferred. potassium, or with an amine, such as trometamol, or the salts of arginine, lysine, or any physiologically acceptable amine. The functional groups optionally present in the molecule of the compounds of formula (I) and in the reaction intermediates, can be protected ester, either permanently or temporarily, by protective groups that ensure a univocal synthesis of the desired compounds . By temporary protective group of amines, alcohols or carboxylic acids is meant: protective groups such as those described in Protective Groups in Organic Synthesis, Greene T. W. and Wuts P. G. M., ed. John Wiley and Sons, 1991 and in Protecting Groups, Kocienski P. J., 1994, Georg Thieme Verlag. The compounds (I) can include precursor groups of other functions that are subsequently generated in one or more different steps. The compounds of formula (I) in which R, represents a cyclohexyl (C 1 -C 3) alkyl are preferred compounds. Equally preferred are the compounds of formula (I), in which the phenyl in position 5 of the triazole is preferably substituted by a methoxy in position 2 and 6, and by a methyl in position 4. And even more preferred, are the compounds of formula (I) in which the phenyl in position 5 of the triazole is preferably substituted by a methoxy in position 2 and 5 and by a methyl or a chlorine in position 4. Particularly preferred are compounds of the formula: wherein R. ,, R4, X ,, X2, X3 and X4 are as defined for (I); one of its salts or solvates. Among those compounds, those in which: re presents 2, 6-d imet oxy-4-methyl nyl. More particularly, the compounds of the formula are preferred: wherein R, and R4 are as defined for (I); one of its salts or solvates. Very preferred is the compounds of the formula: wherein R ,, R4, Y1t Y2 and Y3, are as defined for (I), and X2 represents methyl or a chlorine atom, one of its salts or solvates. The present invention also relates to a process for the preparation of the compounds of formula (I), which comprises the reaction of an aminotriazole of the formula: in which R X X2, X3 and X4 are as defined for (I) • either with an indole carboxylic acid derivative of formula wherein R4, Y ,, Y2 and Y3 are as defined for (I); • either with an indole carboxylic acid derivative of formula: in which Y. ,, Y2 and Y3 are as defined for (I) and R'4 is a precursor group of R4, in which case the compound of the formula is formed as an intermediate: wherein R1t X ,, X2, X3, X4, Y ,, Y2 and Y3 are as defined for (I) and R'4 is a precursor group of R4, where R4 is as defined for (I) ); to obtain the compounds of formula (I), one of their salts or solvates. The intermediates (I ') lead to the compounds of formula (I) by transformation of the group R'4 into R4, which is used in a manner known per se, according to conventional procedures is organic chemistry. The aminotriazoles of formula 7 constitute key, novel intermediates useful for the preparation of the compounds (I) and are an object of the invention. The starting products are commercially available or prepared according to the methods mentioned previously. The following scheme 1 illustrates a synthesis route of the compounds of formula 7. The following scheme 2 illustrates the preparation of the compounds of formula (I) starting from the aminotriazoles of formula 7.

SCHEME 1: PREPARATION OF THE 3-AMINOTRIAZOLES SUBSTITUTED OF FORMULA 7 or NH DClCOCO toluene fc 2) H2N-H-C-MH2H2C03 / p_ridine 1 3) NaOHaq + Very Maypole 7 SCHEME 2; PREPARATION OF THE 3-AMIDOTRIAZOLES (Tí When R4 = - (CH2) nCOOH, the compounds (I) are obtained starting from the corresponding esters, these being obtained in turn from SCHEME 2. When R4 = - (CH2) n-tetrazolyl, the compounds (I) are obtained starting from of the corresponding nitriles of formula: (CH2) n-C = N, by the action of azidotrimethylsilane in the presence of dibutyltin oxide according to the procedure described in J. Org. Chem. 1993, 58, 4139-4141.

The compounds of formula (I ') are obtained according to SCHEME 2, starting from compounds 7 and 8' of formula: wherein R'4 = - (CH2) n- C = N Substituted benzoic acids 1 are commercially available or prepared according to an adaptation of the procedures described in the literature, for example: 1) by regioselective lithiation of substituted benzenes , followed by carboxylation of the lithiated derivative with C02 according to scheme 3: SCHEME 3 with Z, = Br or H according to the nature and / or the position of the substituents X ,, X2, X3, X4 according to: N. S. Narasimhan ei a /., Indian J. Chem., 1973, 11, 1192; R. C. Change to the., Austr. J. Chem., 1991, 44, 1465; T. de Paulis et al., J. Med. Chem., 1986, 29, 61; or 2) by regioselective formylation of benzenes replaced, followed by the oxidation of benzaldehyde substituted by KMnO4, according to SCHEME 4: SCHEME 4 according to the method described by S. B. Matin e al al., J. Med. Chem., 1974, 17, 877; or 3) by haloform oxidation according to R. Levine et al., J. Am.

Chem. Soc, 1959, 72, 1642 of aromatic methyl ketones, obtained by Friedel-Crafts acylation, of substituted benzenes (C.

Bartram et al., J. Chem. Soc, 1963, 4691) or by rearrangement of Acyloxybenzene fries replaced according to S. E. Cremer et al., J. Org. Chem., 1961, 26, 3653, according to schemes 5 and 6 that follow: SCHEME 5 The acids substituted in position 2 by a methoxy can be prepared starting from a substituted phenol derivative by reaction of acetic anhydride in pyridine, followed by a reaction of Fries in aluminum chloride to lead to the hydroxy acetophenone, on which the methyl iodide is reacted in alkaline medium to finally obtain, by a haloform reaction, the acid 1 ' expected according to SCHEME 6 that follows: SCHEME 6 CH3I / OH r NaOH or KOHBr2 The benzamidoguanidine 2 is obtained by acylation of aminoguanidine hydrogencarbonate by benzoic acid chloride obtained starting from benzoic acid 1 by conventional procedures (SOCI2, oxalyl chloride in an inert solvent), according to an adaptation of the procedure described by E. Hoggarth, J. Chem. Soc, 1950, 612. It can also be obtained according to a variant described in this same publication, according to the following SCHEME 7: SCHEME 7 The thermal cyclization of benzamidoguanidine 2 in a high-boiling solvent, such as diphenyl ether, leads to aryl-5-amino-3-triazole 3 according to an adaptation of the method described by E. Hoggarth, J. Chem. Soc. , 1950, 612. Protection of the primary amino function of triazole 3 in the form of diphenylimine leads to the N-protected triazole 4, according to an adaptation of a procedure described by MJ O'Donnell et al., J. Org. Chem., 1982, 47, 2663. It is also possible to obtain compound 4 according to a variant consisting of treating triazole 3, previously transformed into 3 'hydrochloride by diphenylimine, according to the following SCHEME 8: SCHEME 8 The N-alkylation of diphenyliminothiazole 4, by an alkyl halide R, X, under phase transfer conditions (strong base in concentrated aqueous solution, in the presence of a non-miscible organic co-solvent and a quaternary ammonium catalyst) largely leads to triazole 5, accompanied by the very minor triazole 6. The strong bases used may be aqueous solutions of NaOH or KOH in concentrations of 6 M to 12 M. The cosolvent may be toluene, benzene and quaternary ammonium chosen from any quaternary ammonium salt and, more precisely, TBAB (tetrabutylammonium bromide). a) The N-alkylation of diphenyliminotriazole 4 can be carried out in a non-aqueous medium (dimethylformamide, tetrahydrofuran for example) in the presence of a strong base such as K2C03 or NaH. b) It is also possible to use a variant such as that described in E. Akerblom, Acta Che., Scand., 1965, 19, 1142, which employs an alkylating agent in an alcohol such as ethanol in the presence of a solid strong base such as KOH or NaOH.

Triazole 5 is very easily separated from its isomer 6 by chromatography on a silica gel column or flash chromatography, depending on the nature of the R group. The olive of the product 5, obtained after the separation of its minor isomer, is operated in acid aqueous medium such as 1N HCl, according to an adaptation of the method described by J. Yaozhong et al., Tetrahedron, 1988, 44, 5343 or MJ O'Donnell et al., J. Org. Chem., 1982, 47, 2663. It makes it possible to obtain the N-alkylated amino-3-triazole in position 1 of formula 7. The carboxylic indoles of formula 8 have been prepared according to procedures described in patent No. EP 611766 in accordance with next SCHEME 9: SCHEME 9 The carboxylic characters 8 'in which R'4 = - (CH2) n - C = N have been prepared according to an analogous procedure presented in the following SCHEME 9a: SCHEME 9a 11 NaH X (CH2) nC = N 8 ' The characters 11 are commercial or prepared according to an adaptation of the procedures described in the literature, for example according to L. Henn et al., J. Chem. Soc.

Perkin Trans. I, 1984, 2189 according to the following SCHEME 10: SCHEME 10 11 or also, for example, according to the Fischer synthesis (V. Prelog eí al., Helv. Chim. Acta., 1948, 31, 1178) according to the following SCHEME 11: SCHEME 11 EtOH reflux CH3C? C ?? C2H3 or also, according to the synthesis of Japp-Klingemann (H. Ishii et al., J. Chem. Soc. Perkin, Trans. 1, 1989, 2407) according to the following SCHEME 12: SCHEME 12 The aforementioned compounds of formula (!) Also include those in which one or more hydrogen, carbon or halogen atoms, especially chlorine or fluorine atoms, have been replaced by their radioactive isotope, for example tritium or the carbon-14. Said labeled compounds are useful in research work, metabolism or pharmacokinetics, in biochemical tests as receptor ligand. The compounds of formula (I) have been subject to In vitro binding studies to the CCK-A and CCK-B receptors, using the method described in Europ. J. Pharmacol., 1993, 232, 13-19. The agonist activity of the compounds against the CCK-A receptors has been evaluated in vitro in 3T3 cells expressing the human CCK-A receptor, by measuring the mobilization of intracellular calyce ([Ca "],), according to with a technique derived from that of Lignon MF et al., Eur. J. Pharmacol., 1993, 245, 241-245.Calcium concentration [Ca ++] ¡is evaluated with Fura-2 by means of the double method excitation wavelength The ratio of the fluorescence emitted at two wavelengths gives the concentration in [Ca ++ J, after sampling (Grynkiewiez G. et al., J. Biol. Chem., 1985, 260 , 3440-3450) The compounds of the invention stimulate [Ca ++] partially or totally, such as CCK, and therefore behave as agonists of the CCK-A receptor. A study of the agonist effect of the compounds has been carried out. on gastric emptying, as follows Solid 18-hr female albino Swiss CD 1 is fasted for 18 hours (20-25 g). On the day of the experiment, the products are administered intraperitoneally (in suspension in a solution of 1% carboxymethylcellulose or 0.6% methylcellulose) or the corresponding vehicle, 30 minutes before the administration of a coal meal. , (0.3 ml per mouse of a suspension in water of 10% carbon powder, 5% gum arabic and 1% carboxymethylcellulose) or orally one hour before. Mice are sacrificed 5 minutes later by cervical dislocation, and gastric emptying is defined as the presence of carbon in the intestine beyond the pyloric sphincter (Europ. J. Pharmacol., 1993, 232, 1319).

The compounds of formula (I) block the gastric emptying partially or completely as the same CCK, and thus behave as agonists of the CCK receptors. Some of them, have an ED50 (effective dose that induces 50% of the effect of CCK) lower than 0.1 mg / kg intraperitoneally. A study of the agonist effect of the compounds on the contraction of the gallbladder has been carried out in the following manner. Swiss albino CD1 female mice (20-25 g) are subjected to solid fasting for 24 hours. On the day of the experiment, the products are administered orally (in suspension in a solution of 1% carboxymethylcellulose or 0.6% methylcellulose) or the corresponding vehicle. The mice are sacrificed by cervical dislocation, one hour after the administration of the products and the biliary vesicles are removed and weighed. The results are expressed in mg / kg of body weight (Europ.

Pharmacol., 1993, 232, 13-19). The compounds of formula (I) contract the gallbladder partially or completely as the same CCK, and thus behave as agonists of the CCK receptors. Some of them have ED50 (effective dose that induces 50% of the decrease in weight of vesicles observed with CCK) less than 0.1 mg / kg orally. Accordingly, the compounds of formula (I) are used, as agonists of CCK-type A receptors, for the preparation of medicaments for the treatment of diseases whose treatment requires stimulation by total or partial agonism of CCK A receptors. cholecystokinin More particularly, the compounds of formula (I) are used for the manufacture of medicaments intended for the treatment of some disorders of the gastrointestinal area (prevention of gallstones, irritable bowel syndrome) of eating behavior, of obesity, and associated pathologies such as diabetes and hypertension. The compounds (I) induce a state of satiety, and in this way they are used to treat eating disorders, regulate appetite and reduce food intake, treat bulimia, obesity and cause weight loss. Compounds (I) are also useful in disorders of emotional, sexual and amnestic behavior, psychosis and in particular, schizophrenia, in Parkinson's disease, in tardive dyskinesis. They can also serve in the treatment of appetite disorders, that is to regulate the desires of consumption, in particular in the consumption of sugars, carbohydrates, alcohol or drugs and more widely, appetizing ingredients. The compounds of formula (I) are not very toxic; his Toxicity is compatible with its use as a medicine for the treatment of the disorders and diseases mentioned above. No signs of toxicity have been observed with these compounds in pharmacologically active doses, and their toxicity is therefore compatible with their medical use as medicines. Therefore, the present invention also has for its object pharmaceutical compositions containing an effective dose of a compound according to the invention or a pharmaceutically acceptable salt thereof, and a suitable excipient. Said excipients are chosen according to the desired pharmaceutical form and mode of administration. In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal, rectal or intraocular administration, the active principles of formula (I) cited above, or their eventual salts, can be administered under unitary forms of administration, in admixture with classical pharmaceutical supports, to animals and humans for the prophylaxis or treatment of the above mentioned disorders or diseases. Suitable unit dosage forms comprise oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intranasal administration forms, administration forms subcutaneous, intramuscular or intravenous and forms of rectal administration. For topical application, the compounds according to the invention can be used in creams, ointments, lotions or eye drops. In order to obtain the prophylactic or therapeutic effect sought, the dose of active ingredient may vary between 0.01 and 50 mg per kg of body weight per day. Each unit dose may contain from 0.5 to 1000 mg. Preferably from 1 to 500 mg, of active ingredients in combination with a pharmaceutical carrier. This unit dose may be administered 1 to 5 times per day so as to administer a daily dose of 0.5 to 5000 mg, preferably 1 to 2500 mg. When preparing a solid composition in the form of tablets, the main active ingredient is mixed with a pharmaceutical carrier, such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose, with a cellulose derivative, or other suitable materials or can even be treated in such a way that they have a prolonged or delayed activity and continuously release a predetermined amount of active principle. capsules by mixing the active ingredient with a diluent and pouring the obtained mixture into soft or hard capsules. A preparation in the form of syrup or elixir or for administration in the form of drops may contain the active ingredient together with a sweetener, preferably caloric, methylparaben and propylparaben as an antiseptic, as well as an agent that flavors and an appropriate colorant. Powders or granules dispersible in water may contain the active ingredient mixed with dispersing agents or wetting agents, or suspending agents, such as polyvinylpyrrolidone, as well as sweeteners or flavor correctors. For rectal administration, suppositories are used which are prepared with binders that melt at rectal temperature, for example cocoa butter or polyethylene glycols. For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile and injectable solutions containing pharmacologically compatible dispersing agents and / or humectants, for example propylene glycol or butylene glycol, are used. The active principle can also be formulated in the form of microcapsules, optionally with one or more carriers or additives, or with matrices such as a polymer or a cyclodextrin (patch, sustained-release forms). The compositions according to the invention can be used in the treatment or prevention of various conditions where CCK is of therapeutic interest. The compositions of the present invention can contain, in addition to the aforementioned formula (I) products, or their pharmaceutically acceptable salts, other active ingredients that may be useful in the treatment of the disorders or diseases indicated above. Advantageously, the compositions of the present invention contain a product of formula (1.1), (1.2) or (1.3) mentioned above, or one of its pharmaceutically acceptable salts, solvates or hydrates.

PREPARATION OF THE SYNTHESIS INTERMEDIARIES A. PREPARATION OF ACIDS (VARIANTS) 2,5-Dimethoxy- = me_ilbenzo_co acid (Compound A.1) a) 2,5-Dimethoxy-4-methylbenzaldehyde After 40 minutes of stirring at room temperature of a mixture of 8, 5 ml of N-methylformanilide (0.068 mole) and 6.3 ml of phosphorus trichloride (0.068 mole) are charged with 17.8 g of 2,5-dimethoxytoluene (0.117 mole). The reaction mixture is heated for 6 hours at 50 ° C then, after bringing the temperature to 2.0 ° C, it is hydrolyzed by means of 100 ml of 10% aqueous sodium acetate solution, extracted twice with diethyl ether and concentrated. The residue is taken up again by means of an aqueous solution of sodium hydrogen sulfite, and extracted twice with diethyl ether. The aqueous phase is made alkaline (pH = 12) to give white crystals; F = 83 ° C; Performance = 67%. b) 2,5-Dimethoxy-4-methylbenzoic acid. 23.86 g (0.132 mole) of 2,5-dimethoxy-4-methylbenzaldehyde in solution in 500 ml of water is heated at 75 ° C, and 29.3 g. g (0.185 mole) of potassium permanganate in solution in 500 ml of water. The reaction mixture is left for 2 hours at 75 ° C, then the insoluble is filtered off hot, after adjusting the pH to 10 with a 10% solution of sodium hydroxide, and rinsing three times with 80 ml of Hot water. The filtrate is cooled, the formed precipitate is filtered, dried under vacuum at 40 ° C to obtain white crystals; F = 120 ° C; Performance = 71%. 2,5-Dimethoxy-4-chlorobenzoic acid (Compound A.2) a) (2,5-dimethoxy-4-chlorophenyl) methyl ketone To 2 liters of carbon tetrachloride, 162.5 g of trichloride is added at room temperature of aluminum (1.2 mol), then at 0o C, dropwise, 82 ml of acetyl chloride (1.2 mol), then 200 g of 1,4-dimethoxy-2-chlorobenzene (1.2 mol) . The reaction mixture is left for 3 and a half hours at 0 ° C, then hydrolyzed by means of 700 ml of water. The organic phase is washed with a 2 M sodium hydroxide solution, dried over anhydrous sodium sulfate and concentrated. The semicrystalline residue is taken up in petroleum ether, filtered, dried to obtain white crystals; F = 96 ° C; Yield = 70%. b) 2,5-dimethoxy-4-chlorobenzoic acid To 800 ml of water, 278 g of potassium hydroxide (4.96 mol) are added, then at 50 ° C, 84 ml of bromine (1.6 mol) drop drop. The reaction mixture is left for one hour at room temperature. The aqueous solution of sodium hypobromite obtained is added to 107 g of (2,5-dimethoxy-4-chlorophenyl) methyl ketone (0.494 mol) in solution in 1.5 liters of 1,4-dioxane. After one hour at 20 ° C, the reaction mixture is heated at reflux for one hour. When the reaction is finished, 100 ml of an aqueous solution of sodium hydrogensulfite are introduced, then the solvent is evaporated. The residue is acidified by means of a 6N hydrochloric acid solution, then extracted twice with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate, and concentrated. The residue is concentrated in diisopropyl ether, to obtain white crystals; F = 160 ° C; Yield = 91%. 2,6-Dimethoxy-4-methylphenylbenzoic acid (Compound A.3) Dissolve 231.6 g (1.5 moles) of 3,5-dimethoxytoluene in 1 liter of diethyl ether, then add dropwise under nitrogen at room temperature, 1 liter of a 1.6 N solution of butyl lithium (1.6 moles) in hexane. The reaction mixture is left for 18 hours at room temperature then, after cooling to -30 ° C, 1 liter of diethyl ether is added and carbonated gas is bubbled for one hour, maintaining always the temperature at -30 ° C. The reaction mixture is taken again by means of 6 liters of a 2M sodium hydroxide solution, the aqueous phase is decanted, and acidified with a 6N hydrochloric acid solution. The formed precipitate is filtered, rinsed with water and dried under vacuum at 40 ° C to obtain white crystals; F = 187 ° C; Performance = 88%.

B. PREPARATION OF THE BUSTED INDICES AND THEIR VARIANTS Preparation of 5-methyl-1H-2-indole ethyl carboxylate (Compound B.1) 1st method: (Japp-Klingemann method): At -5o C, 7.2 g (0.104 mole) of sodium nitrite in solution are added in 40 ml of water, over a mixture of 10.7. g (0.1 mol) of 4-methiananiline, 74 ml of 12 N hydrochloric acid and of 140 ml of water. The reaction mixture is stirred for 15 minutes at -5 ° C, and neutralized by the addition of 8.1 g of sodium acetate. In a trich, 12.33 g (0.085 mole) of ethyl a-methylacetoacetate, 80 ml of ethanol are introduced, then at 0 ° C 4.8 g (0.085 mole) of potassium hydroxide in solution in 20 ml of water and 100 g of ice. To this reaction mixture, the diazonium solution prepared previously is added dropwise at 0 ° C, and left for 18 hours at 0 ° C. The aqueous phase is extracted 4 times with 50 ml of ethyl acetate, the organic phases are combined and dried over anhydrous sodium sulfate. The residue is taken by 100 ml of toluene and 16.3 g (0.085 moles) of paratoluenesulfonic acid monohydrate. It is then slowly heated to 110 ° C and this temperature is maintained for 5 hours. It is left to cool, then a saturated sodium carbonate solution is added, the solution is discarded by filtration, the organic phase is decanted, dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, and the elution is carried out. Dichloromethane / cyclohexane 30/70 (v / v) to obtain beige crystals; F = 94 ° C; Performance = 25%.

Preparation of ethyl 4-methyl-1 H-2-indolecarboxylate (Compound B2) 2nd method: - Step 1: preparation of azide 9.3 g (0.405 mole) of sodium are added, in portions, to 200 ml of ethanol. To this solution of ethanolate in ethanol, 16.2 g (0.135 mole) of orthotolualdehyde in solution are introduced dropwise at -20 ° C into 52.2 g (0.405 mole) of ethyl azide acetate. After 2 hours at -10 ° C, the reaction mixture is poured into 400 ml of water, and the formed precipitate is filtered. It is dried 18 hours at 40 ° C under vacuum to obtain white crystals; F = 55 ° C; Performance = 78%. - Stage 2: cyclization of azide 19.5 g (0.0844 mole) of the azide prepared according to step 1, in portions, are added to 100 ml of xylene heated at 140 ° C. After the addition is complete, the reaction mixture is left for 1 hour at 140 ° C. The xylene is concentrated and the residue is taken up with isopropyl ether, filtered, dried 18 hours under vacuum at 40 ° C, to obtain white crystals; F = 141 ° C; Performance = 62%.

Preparation of 5-ethyl-1 H-2-indolecarboxylic acid (according to the Fischer method) (Compound B.3) 3rd method: Stage 1: 4-ethylphenylhydrazine hydrochloride is added to 24.2 g (0.2 mole) ) of 4-ethylaniline, 150 ml of water and 160 ml of 12N hydrochloric acid. The mixture is cooled to 0 ° C, then 14 g (0.2 mol) of sodium nitrite in solution in 140 ml of water is introduced dropwise. After 1 hour at 0 ° C, 112 g (0.496 mole) of stannous chloride dihydrate in solution in 90 ml of 12 N hydrochloric acid is added to the reaction mixture at -10 ° C. at -10 ° C, the mixture is reacted in the filter to obtain a brown solid; F = 198 ° C; Yield = 95%. - Stage 2: 2- [2- (4-Ethylphenyl) hydrazono] ethyl propanoate is added to 34.5 g (0.2 mol) of 4-ethylphenylhydrazine hydrochloride prepared previously in suspension in 500 ml of ethanol, 23 ml (0.2 mol) of ethyl pyruvate, and the reaction mixture is heated for 3 hours at reflux. The temperature is then brought to 20 ° C, and the ethanol is evaporated. The solid residue is wash with pentane, dry at 40 °, C under vacuum to obtain a colorless liquid; Yield = 94%. Step 3: 5-Ethyl ethyl 1 H-2-indolecarboxylate To 44 g (0.188 mole) of hydrazone previously prepared in suspension in 300 ml of toluene, is added over 7 hours, in portions, at reflux, 19 g (0.1 mol) of paratoluenesulfonic acid monohydrate. The temperature is brought to 20 ° C, the insoluble is separated by filtration and rinsed with toluene. The filtrate is washed with a saturated aqueous solution of potassium carbonate; it is decanted, dried over anhydrous sodium sulfate and concentrated. The residue is purified by chromatography on a column of silica gel, eluting: dichloromethane / cyclohexane 5/5 (v / v) to obtain beige crystals; F = 94 ° C; Yield = 51%. Step 4: 5-Ethyl I-1 H-2-indolecarboxylic acid To 150 ml of 1,4-dioxane, 15.8 g (0.073 mol) of ethyl 5-ethyl-2-indocarboxylate prepared according to the step are added. 3, then 45 ml of a 2M solution of sodium hydroxide (0.09 mole). The reaction mixture is left for 48 hours at room temperature. After evaporation of 1,4-dioxane, the residue is taken up by means of a 6 N hydrochloric acid solution, the precipitate formed is filtered, dried under vacuum at 60 ° C to obtain the 5-ethyl-1 H acid. -2-indolecarboxylic in the form of white crystals; F = 184 ° C; Yield = 92%.

PREPARATION OF ACIDS 1 H-2-INDOLCARBOXÍLICOS N- ALQUILOS -Ethyl-1- (methoxycarbonylmethyl) 1H-2-indolecarboxylic acid- (Compound B.4) - Stage 1: 5-Ethyl-1H-2-benzoyl incarboxylate To 70 ml of dimethylformamide, 12.7 is added successively g (0.067 mol) of 5-et i I-1 H-2-indocarboxylic acid, 10 ml of 1,8-diazabicyclo [5.4.0] undec-7-ene (0.067 mol). The reaction mixture is left for 40 minutes at 0 ° C, then 10.6 ml of benzyl bromide (0.089 mol) is introduced dropwise. After 18 hours of reaction at room temperature, the reaction mixture is poured into 300 ml of water, the formed precipitate is filtered, rinsed with water, dried for 18 hours at 50 ° C under vacuum to obtain yellow crystals; F = 99 ° C; Performance = 90%. - Step 2: 5-Ethyl-1- (methoxycarbonylmethyl) -1H-2-benzyl indolecarboxylate To 1.5 g (0.031 mole) of 50% sodium hydride in suspension in oil, add 75 ml of dimethylformamide then , by portions, 7.9 g (0.0283 moles) of benzyl 5-ethyl-1H-2-indolecarboxylate prepared according to step 1. After 40 minutes at 0 ° C, 3.5 is added dropwise ml (0.0315 mol) of methyl bromoacetate, and the reaction mixture is left for 2 hours at 20 ° C. 300 ml of ethyl acetate are added, and it is washed with 2x300 ml of water, then decanted, the organic phase is dried on anhydrous sodium sulfate and concentrate. 9.5 g of colorless oil are obtained; Yield = 95%. Step 3: 5-Ethyl-1- (methoxycarbonylmethyl) -1H-2-indolecarboxylic acid To 9.5 g (0.0269 moles) of 5-ethyl-1- (methoxycarbonylmethyl) -1H-2-benzyl indolecarboxylate prepared according to step 2 in solution in 150 ml of ethanol, 2.5 g of 10% Pd / C, then 40 ml of cyclohexane (0.3595 moles). The reaction mixture is heated for 2 hours at 70 ° C, then the temperature is brought to 20 ° C. The reaction mixture is filtered on talc and the filtrate is evaporated to dryness. The residue is dried for 18 hours at 40 ° C under vacuum, to obtain beige crystals; F = 181 ° C; Performance = 90%. Proceeding in accordance with the above PREPARATIONS, starting from the appropriate synthesis intermediates, Compounds B5 to B70 are synthesized in the following BOX I.

TABLE 1 4,5-Dimethyl-1- (3-cyanopropy) -1H-2-indolecarboxylic acid (Compound B71) - Step 1: 4,5-Dimethyl-1- (3-cyanopropyl) -1 H-2-indocarboxylate ethyl To 1.92 g (0.040 mole) of 50% sodium hydride in suspension in oil, 75 ml of dimethylformamide are added, then, in portions, 7.9 g (0.0363 mole) of 4,5-dimethyl- 1 ethyl H-2-indole carboxylate. After 40 minutes of stirring at 0 ° C, 4.0 ml (0.040 mol) of 4-bromobutyronitrile is introduced dropwise, and the reaction mixture is kept for 2 hours at 20 ° C. 300 ml of ethyl acetate are added, and it is washed twice with 300 ml of water, then it is decanted, the organic phase is dried over anhydrous sodium sulfate and concentrated. 9.8 g of colorless oil are obtained; Yield = 95% - Stage 2: 4,5-Dimethyl-1- (3-cyanopropyl) -1 H-2-indolecarboxylic acid To 150 ml of 1,4-dioxane, 9.8 g (0.0345 mole) of ethyl 4,5-dimethyl-1- (3-cyanopropii) -1 H-2-indocarboxylate are added, then 25 ml of a 2M solution of sodium hydroxide (0.05 mol). The reaction mixture is maintained for 48 hours at room temperature. After the evaporation of 1,4-dioxane, the residue is taken up with a 6M hydrochloric acid solution, the formed precipitate is filtered, dried under reduced pressure at 60 ° C, to obtain the 4,5-dimethyl acid. -1- (3-Cyanopropyl) -1 H-2-indolecarboxylic acid in the form of white crystals; F = 175 ° C. performance = 92%. In the same way, compounds B72 to B75 are prepared, which are presented in the following FIG. 1 bis. TABLE I is C. PREPARATION OF BENZAMIDOGUANIDINE DERIVATIVES Preparation of 2,6-dimethoxy-4-methylbenzamidoguanidine (Compound C.1) To 356 g (1.8 moles) of 2,6-dimethoxy-4-methylbenzoic acid in suspension in 1.5 liters of toluene, add 1 ml of dimethylformamide then, dropwise, 190 ml of chloride oxalyl (2.16 moles). The reaction mixture is left for two hours at room temperature, then evaporated to dryness. The crystalline residue is added portionwise to a suspension of 293.8 g of aminoguanidine hydrogen carbonate (2.16 moles) in 2.5 liters of pyridine at + 5 ° C, and left for 18 hours at 20 ° C. The reaction mixture is evaporated to dryness, then the residue is taken up again by means of 1 liter of a 2 M sodium hydroxide solution. The precipitate is filtered and rinsed with a minimum of water, then dried under vacuum at 60.degree. ° C to obtain a crystalline residue; F = 222 ° C; Performance = 81%.

D. PREPARATION OF DERIVATIVES 3-AMINOTRIAZOLES 3-Amino-5 (2,6-dimethoxy-4-methylphenol) 1,2,4-triazole (Compound D.1) To 230 g (0.91 mol) of 2,6-dimethoxy-4-methylbenzamidoguanidine, 2 liters of diphenylether are added, then the reaction mixture is heated for 5 minutes at 220 ° C. The temperature is brought to 80 ° C, then the precipitate is filtered, rinsed with diisopropyl ether, and dried under vacuum at 60 ° C, to obtain crystals; F = 286 ° C; Yield = 93%. Proceeding in accordance with this PREPARATION, and using the appropriate starting products, Compounds D2 to D11 are synthesized in the same manner as described in the following Table II: PICTURE p E. PREPARATION OF DIFENILIMINO DERIVATIVES Preparation of N- [3- (2,6-d-imethoxy-4-methyl If in i I) -1 H-1, 2,4-triazol-5-yl] -N-diphenylmethyleneamine (Compound E.1) Warm to 140 ° C, 105 g (0.45 moles) of 3-amino-5- (2,6-dimethoxy-4-methylphenyl) -1, 2,4-triazole in suspension in 200 ml of xylene and 150 g (0.9 mol) of benzophenoneimine, for 48 hours, under argon stream. The temperature is brought to 80 ° C, then Pour the reaction mixture into 4 liters of isopropyl ether, filter the formed precipitate, rinse with diisopropyl ether, and dry for 18 hours at 50 ° C; F = 126 ° C; Performance = 90%.

TABLE m F. PREPARATION OF THE 3-AMINO TRIAZOL-1 - SUBSTITUTE Preparation of "1- ('2" -cic • lo • hex "ile-AtL.il *) - 5 - (, 2 ~, 6? _ Dimethoxy-4-methylphenyl) - 1 H-1_2,4-triazole -3-amine (Compound F.1) a) N-alkylation of the triazole To 400 ml of toluene, successively add 300 ml of a 6N aqueous solution of sodium hydroxide, 24 g (0.06 moles) of N- [3- (2,6-dimethoxy-4-methylphenyl) -1 H-1, 2,4-triazol-5-yl] -N-diphenyl-methyleneamine and 2.7 g of tetrabutylammonium bromide. To the reaction mixture heated to 70 ° C, 17 g (0.09 mol) of 2-bromoetylcyclohexane is added dropwise. The reaction is maintained for 2 hours at 80 ° C. The organic phase is decanted, dried over anhydrous sodium sulfate, and evaporated to dryness. The residue is chromatographed on a column of silica gel, eluting with a toluene / ethyl acetate mixture 90/10 (v / v). 21.4 g of colorless oil are obtained; Yield = 70%. b) Hydrolysis of the diphenylimine A function 10.3 g (0.02 mole) of N- [1- (2-cyclohexylethyl) -5- (2,6-dimethoxy-4-methylphenyl) -1H-1,2, 4-triazol-3-yl] -N-diphenylmethyleneamine in solution in 200 ml of methanol, 100 ml of a 1 N solution of hydrochloric acid are added. The reaction mixture is left for 18 hours at room temperature, then evaporated to dryness. The oily residue is concreted in diethyl ether, and the precipitate obtained is filtered and dried under vacuum at 40 ° C; F = 136 ° C (hydrochloride); Performance = 90%.

TABLE IV TABLE IV (cont'd 1) TABLE IV (cont 2) TABLE IV (cont.3) In the same way, it is prepared from the compound E10, 1- (2-cyclohexylethyl) 5- (2,6-dimethoxy-4,5-d imeti If enyl) -1 H -1,2,4-triazole-3 -amine (Compound F 38); F = 180 ° G. PREPARATION OF AZID AMIDOTRI DERIVATIVES WITH NON-NON-SUBSTITUTE INDONES Synthesis of N- [1 - (2-chlorobenzyl) -5- (2,6-dimethoxy-4-methylphenyl) -1 H-1,2,4- triazol-3-yl] 5-chloro-1H-2-indolecarboxamide (Compound G.1) To a solution of 1 ml of pyridine (0.013 mol) in 30 ml of methylene chloride is added at 0 ° C, 0, 2 ml of thionyl chloride (0.0028 mol). After 15 minutes at 0 ° C, 500 mg (0.0025 mol) of 5-chloroindolcarboxylic acid are introduced, and the reaction mixture is left for 30 minutes at 0 ° C. To the acyl chloride formed is added 0.91 g (0.0028 mol) of 1- [(2-chlorophenyl) methyl] -5- (2,6-dimethoxy-4-methylphenyl) -1H-1 hydrochloride. , 2,4-triazol-3-amine, and left for 18 hours at 20 ° C.

The reaction mixture is washed with a 1M solution of sodium hydroxide. The organic phase is dried over anhydrous sodium sulfate and evaporated to dryness. The residue is chromatographed on silica gel, eluting: dichloromethane / methanol 95/5 (v / v) to obtain 0.980 g of crystals; F = 262 ° C; Performance = 73%.

TABLE V TABLE V (cont. 1) TABLE V (cont.2) H. PREPARATION OF AMINOTRIAZOL DERIVATIVES WITH N-SUBSTITUTE INDOORS EXAMPLE 1 2- [2- ( { [1- (2-Cyclohexylethyl) -5- (2,6-d-imethoxy-4-methylphenyl) -IH-1,2,4-triazol-3-yl] amino .}. carbonyl) -5-ethyl-1H-indole-1-methyl-methyl acetate To 15 ml of dichloromethane, 1 ml of pyridine (0.013 mol) and 0.21 ml of thionyl chloride (0.00029) are successively added. moles). After 15 minutes at 0 ° C, 0.627 g of 5-ethyl-1-methoxycarbonylmethyl-1H-2-indolecarboxylic acid (0.degree., 0024 mol), then 0.9 g of 1- (2-cyclohexylethyl) -5- (2,6-dimethoxy-4-methylphenyl) -1H-1, 2,4-triazol-3-amine hydrochloride. . The reaction mixture is left for 18 hours at room temperature, then acid wash, then basic wash. The organic phase is dried over anhydrous sodium sulfate and concentrated. The oily residue is chromatographed on a column of silica gel, eluting with a mixture: dichloromethane / methanol 98.5 / 1.5 (v / v) to obtain a white powder; F = 191 ° C; Performance = 87%.

EXAMPLE 2 2- [2- (. {M- (2-cyclohexylethyl) -5- (2,6-dimethoxy-methylphenyl) -1H-1,2,4-triazol-3-yl] amino} acid. carbonyl) -5-ethyl-1H-indol-1-yl] acetic acid To 530 mg (0.0009 mol) of 2- [2- ( { [1- (2-cyclohexylethyl) -5- (2,6-dimethoxy 4-methylphenyl) -1H-1,2,4-triazol-3-yl] amino.} Carbonyl) -5-ethyl-1 H-indole-1-yl-methyl-acetate prepared in accordance with EXAMPLE 1, in Solution in 50 ml of methanol is added 1.8 ml (0.0018 mol) of a 1N solution of sodium hydroxide. After 18 hours at room temperature, the reaction mixture is evaporated to dry. The residue is taken up in ethyl acetate and a solution of 0.5 N hydrochloric acid. The organic phase is decanted and dried over anhydrous sodium sulfate and concentrated. The residue is purified by chromatography on a column of silica gel, eluting with a mixture: dichloromethane / methanol 92/8 (v / v) to obtain white crystals; F = 198 ° C; Performance = 91% Proceeding in accordance with the aforementioned EXAMPLES 1 and 2, EXAMPLES 3 to 511 described in TABLES VI and VII below are prepared in the same manner, starting from the appropriate intermediaries.

TABLE VI TABLE Vi fcnnf i) TABLE VI fcont. 2) Oi D O VI (cont.3 TABLE VI ícont. 4) CUADR VI co fifteen twenty TABLE VI (cont.

TABLE VI rcont. 7) TABLE VI fcont. 8) TABLE VI fcont. 9) TABLE VI (cont'd T O) TABLE VI fcont.11.

TABLE VI (cont.12) TABLE V? T TABLE VH fcont.1) TABLE VII fcnnt. 2) TABLE VII (cont 3) TABLE VII (cont 4) ';5 TABLE VII (cont. 5) TABLE VII (with 6) TABLE VII (continued 7) TABLE VII fcont. 8) TABLE VI? (cnnt.) Q TABLE VII (cont.10) TABLE VII fcont. OR) TABLE Vp fcont. 12) TABLE VII (cont.

TABLE VII fcont. 14) TABLE VII fcont. fifteen) TABLE VII (cont. 16) TABLE VII (cont'd 17) TABLE VII (cont'd 18) TABLE VII (continued 191) TABLE VII (cont. 20) TABLE VII (cont. 21) TABLE VII (cont. 22) TABLE VH (cont. 23) TABLE VII (cont. 24) TABLE VII (cont. 25) TABLE VII fcont. 26) TABLE VII (cont. 27) TABLE VII fcont. 28) TABLE VII fcont. 29) TABLE VII (cont.30) TABLE VII fcont 31) TABLE VII (cont. 32) TABLE VII (cont. 33) TABLE VII fcont 34) TABLE VII (cont'd 35) TABLE VII (cont. 36) TABLE VII (cont. 37) BOX VH fcopt. 38) TABLE V ?? (cont'd 39) TABLE VII (cont .. 40) TABLE VII (cont 41) TABLE VII (cont 42) TABLE VII (cont 43) TABLE VII (cont 44) TABLE VII (cont. 45) TABLE VII (cont. 46) TABLE VII (copt 47) TABLE VII (cont'd 48) TABLE VII (cont. 49) TABLE VII (cont 50) TABLE VII (cont 51) TABLE VII (cont. 52) TABLE VII ícont. 53) TABLE VH fcont. 54) TABLE VII (cont. 55) TABLE Vp ícont 56) TABLE Vp (item 57) TABLE V ?? (cont. 58) TABLE VII (cont. 59) TABLE VII (cont 60) TABLE VII (cont 61) TABLE VII (cont 62) TABLE VII (cont. 63) TABLE Vp (cont'd 64) TABLE Vp (cont 65) BOX VH (cont. 66) TABLE Vp ícont. 67) TABLE VII ícont. 68) TABLE Vp fcont 69) EXAMPLE 512: N2- [5- (4-c.ooro-2,5-dimethoxyphen.l) -1- (2-cyclohexyethi) -H-1,2,4-tr-azoI-3-yl] carbamoyl) -4.5 -dimeti_-1- [3- (2H-1,2,3,4-tetrazol-5-yl) propyl] -1H-2-indolecarboxamide Stage 1: 4- [2- ( { [1 - (2 -Cyclohexylethyl) -5- (2,5-dimethoxy-4-chlorophenyl) -1H-1,2,4-triazol-3-yl] amino] -carbonyl) -4,5-dimethyl-1H-1-indolyl] butiron Trilo To 15 ml of dichloromethane, 1 ml of pyridine (0.013 mole) and 0.21 ml (0.0029 mole) of thionyl chloride are successively added. After 15 minutes at 0 ° C, 0.615 g of 4,5-dimethyl-1- (3-cyanopropyl) -1H-2-indolecarboxylic acid (0.0024 mol), then 0.9 g of hydrochloride of 1 ( 2-cycloexylethyl) -5- (2,5-dimethoxy-4-chlorophenyl) -1 H-1, 2,4-trilazol-3-amine. The reaction mixture is kept for 18 hours at room temperature, then an acid wash, then a basic wash. The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The oily residue is chromatographed on a column of silica gel, eluting with a dichloromethane / methanol 98.5 / 1.5 (v / v) mixture to obtain a white powder; F = 178 ° C; Performance = 87%. Step 2: N2- [5- (4-chloro-2,5-dimethoxyphenyl) -1- (2-cyclohexylethyl) -1H-1,2,4-triazol-3-yl] -4,5-dimethyl-1 - [3- (2H-1,2,3,4-tetrazol-5-yl) propyl] -1H-indolecarboxamide A 0.720 g (0.0012 mole) of 4- [2- ( { [1 - ( 2-cyclohexylethyl) -5- (2,5-dimethoxy-4-chlorophenyl) -1H-1,2,4-triazol-3-yl] amino.} 3-carbonyl) -4,5-dimethyl- 1 H-1 -indolyl] butyronitrile in solution in 15 ml of tetrahydrofuran, 0.5 ml of azidotrimethylsilane, 0.030 g is added of dibutyltin oxide and heated to reflux for 18 hours. The reaction mixture is allowed to return to room temperature, the tetrahydrofuran is removed under reduced pressure and the residue is chromatographed on a column of silica gel, eluting with a mixture of dichloromethane / methanol 95/5 (v / v) . A white solid is obtained; F = 233 ° C; Performance = 78%. That operating mode described in EXAMPLE 512 is also used for EXAMPLES 303, 304, 316, 317, 356, 357, 361, 362, 363, 368, 369, 392, 394, 395, 430, 431, 432. The salts of potassium and sodium of these compounds are obtained in acetonitrile by the addition of one equivalent of base at room temperature, followed by evaporation under reduced pressure of the solvent, and subsequent drying.

Claims (16)

CLAIMS Compound of formula: wherein: R represents a (C2-C6) alkyl; a group - (CH2) m-G where n ranges from 0 to 5 and G represents a non-aromatic mono- or non-aromatic hydrocarbon group at C3-C13 optionally substituted by one or more (C1-C3) alkyl; a wherein the phenyl group is optionally substituted once or several times by a halogen, by a (C1-C3) alkyl or by a (C1-C3) alkoxy; a group - (CH2) nNR2R3 in which n represents an integer from 1 to 6 and R2 and R3 identical or different represent a (C1-C3) alkyl or constitute with the nitrogen atom to which a morpholino group is attached; piperidino, pyrrolidinyl or piperazinyl; X1t X2, X3 or X4 each independently represents a hydrogen atom, a halogen atom, a (C, -C6) alkyl, a (0, -03) 8100x1 or a trifluoromethyl; it is understood that a single one between X ,, X2, X3 or X4 represents possibly a hydrogen atom; - R4 represents hydrogen, a group - (CH2) nCOOR5 in the which n is as defined above and R 5 represents a hydrogen atom, a (C 1 -C 6) alkyl or a (C 6 -C 10) aryl- (C

1 -C 6) alkyl; a (C1-C6) alkyl; a group - (CH2) nOR5 or a group (CH2) nNR2R3 in which n, R2, R3 and R5 are as defined above; a - (CH2) -n-tetrazolyl group in which n is as defined above, or R4 represents one of those groups in the form of an alkali metal or alkaline earth metal salt; - Y ,, Y2 and Y3 independently represent a hydrogen, a halogen, a (C1-C3) alkyl; a (C1-C3) alkoxy, a nitro, a cyano, (C1-C6) acylamino, carbamoyl, trifluoromethyl, a group COOR6 in which R6 represents hydrogen, or (C1-C3) alkyl; or one of its salts or solvates. 2. Compounds of formula (I) according to claim 1, wherein R ,, R4, X1f X2, X3 and X4 are as defined in claim 1 and Y ,, Y2 and Y3 represent hydrogen; one of its salts or solvates. 3. Compounds of formula (I) according to claim 1, wherein R, and R4 are as defined in claim 1, Y. ,, Y2 and Y3 represent hydrogen; Y represents 2,6-dimethoxy-4-methylphenyl; one of its salts or solvates 4. Compounds of formula (I) according to claim 1, wherein R. ,, R4, Y ,, Y2 and Y3 are as defined in claim 1 and X Sli qT X3 X4 represents 2,6-dimethoxy-4-methylphenyl; one of its salts or solvates. 5. Compound of formula (I) according to claim 1, wherein R. ,, R4, Y ,, Y2 and Y3 are as defined in claim 1 and x- 5X, reprcsenta wherein X2 represents methyl or a chlorine atom; one of its salts or solvates. 6. Formula compound: wherein R1t X ,, X2, X3 and X4 are as defined for (I) in claim 1. 7. Process for preparing a compound of formula (I) according to any of claims 1 to 5 , indistinctly, comprising the step of reacting an aminotriazole of the formula: wherein R ,, X ,, X2, X3 and X4 are as defined for (I) in claim 1, with an indole carboxylic acid derivative of formula 8: wherein R4, Y ,, Y2 and Y3 are as defined for (I) in claim 1, to obtain the compounds of formula (I); one of its salts or solvates. 8. Process for the preparation of a compound of formula (I), according to any of claims 1 to 5, indifferently, comprising the reaction of an aminotriazole of the formula: in which R. ,, X ,, X2, X3 and X4 are as defined for (I) • either with an indole carboxylic acid derivative of formula wherein R4, Y ,, Y2 and Y3 are as defined for (I); • either with an indole carboxylic acid derivative of formula: wherein Y1f Y2 and Y3 are as defined for (I) and R'4 is a precursor group of R4, in which case the compound of the formula is formed as an intermediate: wherein R ,, X ,, X2, X3, X4, Y1: Y2 and Y3 are as defined for (I) and R'4 is a precursor group of R4, where R4 is as defined for ( I). 9. A pharmaceutical composition containing, as an active ingredient, a compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof. 10. A pharmaceutical composition containing, as an active ingredient, a compound according to claim 2 or a pharmaceutically acceptable salt thereof. 11. A pharmaceutical composition containing, as an active ingredient, a compound according to claim 3 or a pharmaceutically acceptable salt thereof. 12. Pharmaceutical composition containing, as active ingredient, a compound according to claim 4 or a pharmaceutically acceptable salt thereof. 13. A pharmaceutical composition containing, as active ingredient, a compound according to claim 5 or a pharmaceutically acceptable salt thereof. 14. Use of a compound according to any of claims 1 to 5, for the preparation of drugs intended to treat eating disorders, obesity and reduction of food intake. 15. Use of a compound according to any of claims 1 to 5, for the preparation of drugs intended to treat late dyskinesis. 16. Use of a compound according to any of claims 1 to 5, for the preparation of drugs intended to treat disorders of the gastrointestinal tract.